The Human Blastocyst Regulates Endometrial Epithelial Apoptosis in Embryonic Adhesion1

Abstract

The implanting blastocyst must appose and adhere to the endometrial epithelium and, subsequently, invade it. Locally regulated uterine epithelial apoptosis induced by the embryo is a crucial step of the epithelial invasion in rodents. To address the physiological relevance of this process in humans, we investigated the effect of single human blastocysts on the regulation of apoptosis in cultured human endometrial epithelial cells (hEEC) in both apposition and adhesion phases of implantation. Here, we report a co-ordinated embryonic regulation of hEEC apoptosis. In the apposition phase, the presence of a blastocyst rescues hEEC from the apoptotic pathway. However, when the human blastocyst adheres to the hEEC monolayer, it induces a paracrine apoptotic reaction. Fas ligand (Fas-L) was present at the embryonic trophoectoderm. Fas was localized at the apical cell surface of hEEC, and flow cytometry revealed that 60% of hEEC express Fas. Neutralizing adhesion assays revealed that the Fas/Fas-L death system may be an important mechanism to cross the epithelial barrier, which is crucial for embryonic adhesion, and the manipulation of this system could have potential clinical implications as an interceptive mechanism.

The Expression and Possible Roles of Chemokine CXCL11 and Its Receptor CXCR3 in the Human Endometrium

“…Embryo-induced apoptosis of epithelial cells is an important mechanism for invading the luminal epithelium and breaching the epithelial barrier; the immediate consequence is that the trophoectoderm come in direct contact with the basement membrane and, then, stromal invasion can proceed (3). The apoptotic mechanism in endometrial epithelial cells is triggered by a direct contact between blastocysts and epithelial cells (3). In view of the present finding that IFN-␥ and CXCL11 induced apoptosis of EEC, we speculate that embryo-derived IFN-␥ kills EEC for implantation and that the apoptotic effect is partially indebted to IFN-␥-induced CXCL11 in EEC.…”

“…Cell death, especially apoptosis, of endometrial epithelial cells occurs in implantation sites not only in mice (43), rats (44), and hamsters (45), but also in humans (3,46). Embryo-induced apoptosis of epithelial cells is an important mechanism for invading the luminal epithelium and breaching the epithelial barrier; the immediate consequence is that the trophoectoderm come in direct contact with the basement membrane and, then, stromal invasion can proceed (3).…”

“…The endometrial epithelium is an important element where the molecular interactions between the embryo and the endometrium are initiated (2)(3)(4). A specific molecular cross-talk between embryo and endometrium has been reported during the human implantation process (5).…”

Early stages of implantation as revealed by an in vitro model

“…Access of the trophectoderm to the lateral epithelial surface is a crucial early step in both humans and rodents (Parr et al 1987, Pampfer & Donnay 1999, Lopata et al 2002. In the apposition phase, the presence of a human blastocyst protects epithelial cells against the apoptotic/displacement pathway, while after adhesion it induces apoptosis (Galan et al 2000). After the mouse blastocyst adheres to the Ishikawa cell monolayer, it similarly appears to induce a displacement reaction in cells in close contact, as is the nature of mouse blastocyst implantation.…”

Estudio de los factores materno-embrionario que determinan la fertilidad y prolificidad en una línea de conejo seleccionada por velocidad de crecimiento

“…A nivel celular, los primeros cambios que se producen en el endometrio materno se han estudiado principalmente en diferentes especies de roedores, además de algunos estudios realizados en humanos, concluyendo que los fenómenos más importantes son fenómenos de apoptosis y proliferación celular (Galán et al, 2000; Aplin y Kimber, 2004). INTRODUCCIÓN …”